386 Case Report Coincidence of Recurrent Hemiparesis and Detection of ALL in a 4-Year-Old Girl: One or Two Diseases? Gleichzeitiges Auftreten rezidivierender Hemiparesen und ALL bei einem 4-jährigen Mädchen: eine oder zwei Krankheiten? Authors M. J. Ege1, 2, L. H. Meyer1, K.-M. Debatin1, K. Stahnke1 Affiliations 1 Key words ▶ acute lymphoblastic ● leukemia ▶ cerebral lymphoma ● ▶ stroke ● ▶ hemiparesis ● Abstract & Zusammenfassung & Stroke like symptoms in children such as hemiparesis are often associated with infection, cranial trauma, cardiac anomalies or sickle cell disease. In childhood leukemia, stroke like symptoms at presentation are rare and normally caused by cerebral bleedings. Here we report a patient who presented with classical stroke symptoms and hemiparesis prior to the diagnosis of acute lymphoblastic leukemia without proven CNS infiltration by leukemic cells. In general, acute leukemia or cerebral lymphoma do not lead to extensive defects of brain tissue. This unusual case suggests that acute lymphoblastic leukemia may present with stroke like CNS symptoms including hemiparesis. Im Kindesalter sind Symptome eines zerebralen Insults wie z. B. eine Hemiparese häufig mit Infektionen, Schädeltraumen, Herzanomalien oder der Sichelzellanämie assoziiert. Dagegen gilt die Hemiparese nicht als Initialsymptom einer Leukämie im Kindesalter. Wir berichten hier über eine Patientin mit klassischen Symptomen eines Hirninfarktes mit Hemiparese in zeitlichem Zusammenhang mit der Diagnose einer akuten lymphoblastischen Leukämie (ALL), ohne Nachweis von Leukämiezellen im ZNS. Grundsätzlich führen weder akute Leukämien noch zerebrale Lymphome zu ausgedehnten Hirngewebsdefekten. Dieser Fallbericht legt nahe, dass sich eine ALL initial mit neurologischen Symptomen eines Hirninfarktes einschl. einer Hemiparese präsentieren könnte. Introduction & ve does not provide an answer to the etiology of the neurologic findings, the second potential explanation would imply a disease variant not yet described. Additionally, the problem that leukemia cells were not found in the cerebrospinal fluid or in brain tissue at any time would have to be faced. Bibliography DOI 10.1055/s-0029-1239534 Klin Padiatr 2009; 221: 386–389 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence PD Dr. Karsten Stahnke Universität Ulm, Klinikum Universitätsklinik für Kinderund Jugendmedizin Eythstr. 24 89070 Ulm Germany Tel.: + 49/731/500 57259 Fax: + 49/731/500 57002 karsten.stahnke@uniklinik-ulm.de Universitätsklinik für Kinder- und Jugendmedizin, University of Ulm, Germany University Children’s Hospital, Munich, Germany We report a case of a girl who presented recurrent hemiparesis after an episode of fever accompanied by leukopenia and moderate anemia followed by progressive neurological symptoms such as generalized seizures and coma. She recovered from these with structural defects and neurological deficits. After six weeks of predomiant neurological symptoms tricytopenia developed and a bone marrow aspirate revealed acute lymphoblastic leukemia (ALL). This finding raises the question of a causal association between the ALL and the initial presentation with stroke like symptoms and hemiparesis. Besides a chronological coincidence without any underlying causal association one might think of a rare variant of ALL with primary intracebral (microvascular?) manifestation, which may have been masked by concomitant treatment with corticosteroids during the stroke episode. While the first alternati- Case study & A four-year-old girl presented to the primary care physician with fever, leukopenia (1.9 × 109/L) and moderate anemia (Hb 93.7 g/L, average of age matched controls: 108 g/L) without hepatosplenomegaly or lymph node enlargement. A platelet count was not determined. She had already presented an episode with high fever and bronchitis two months before, from which she had recovered slowly. Two weeks after having been presented to the primary care physi- Ege MJ et al. Coincidence of Recurrent Hemiparesis and Detection of ALL … Klin Padiatr 2009; 221: 386–389 Downloaded by: Collections and Technical Services Department. Copyrighted material. Schlüsselwörter ▶ akute lymphoblastische ● Leukämie ▶ zerebrales Lymphom ● ▶ zerebraler Insult ● ▶ Hemiparese ● 2 Fig. 1 Cranial imaging during the second admission. A CCT at the onset of neurological symptoms. No specific alterations could be detected, particularly no signs of brain edema. B MRI performed 4 h after lumbar puncture. An extensive infarction of the right hemisphere with midline shift and herniation of the mesencephalon was found. This finding led to an emergency craniotomy. C MRI in the remission phase of the neurological symptoms revealing substantial loss of gray and white matter of the right hemisphere. Rarefication of the peripheral parts of the anterior, medial, and posterior cerebral arteries were found in a vascular MRI, but no stenosis of these vessels was noticed. D CCT at the relapse of the neurological symptoms with prolonged coma: Disseminated hypodense areas were found particularly in the right basal ganglia and the pons. The midline was slightly shifted to the left side. Intracerebral hemorrhages were not present. MRI imaging during the antileukemic treatment E Cranial MRI after eight weeks of chemotherapy at the beginning of the neurologic recovery. Loss of brain tissue and dilatation of the right ventricle had increased in between. In the pons and the basal ganglia small signal-intense structures are found, possibly indicating petechial hemorrhages. F Cranial MRI exhibiting residual brain alterations at the start of the maintenance therapy. cian, the girl complained about severe headache and weakness of the right arm and leg. On arrival at the children’s hospital, the child was conscious, had no fever, displayed no sensitivity alterations and no signs of meningitis. No hemiplegia was detectable but a weakness of the right leg and a pes equinus was noted. Laboratory parameters were normal except for an isolated leukopenia (2.2 × 109/L) with normal blood differential, normal platelet count (165 × 109/L), and a moderate elevation of liver enzymes. The symptoms were transient with the white blood cell count recovering spontaneously and the episode was interpreted as caused by a viral infection. Ten days later the girl was readmitted with a paresis of the left arm and left leg. She did not respond adequately to verbal stimuli. The clinical examination revealed a hypotonic paresis of the left side – in contrast to the previous admission, where hemiparesis was rightsided – a partial left-sided paresis of the facial nerve and a deviation of the eyes to the right. A cerebral computed tomography (CCT) showed no alterations; in particular, no ▶ Fig. 1A) were presigns of cerebral edema or CNS infiltration (● sent. A lumbar puncture performed the following day showed moderately elevated cerebrospinal fluid (CSF) protein (585 mg/L, CSF cellularity 6 × 106 cells/L) and, upon microscopic examination, normal lymphomonocytic cells. In the peripheral blood the white cell count was 2.1 × 109/L, the platelet count was 157 × 109/L and Hb 108.0 g/L. Four hours after lumbar puncture the girl lost consciousness and developed generalized seizures. A magnetic resonance imaging (MRI) exhibited infarction of the right hemisphere with a promi▶ Fig. 1B) nent midline shift and a herniation of the brain stem (● suggestive of increased intracranial pressure. Emergency craniotomy was performed and dexamethasone was administered for treatment of the cerebral edema. A brain biopsy obtained two days later showed perivascular hemorrhage, edema, moderate reactive astrocytosis and disseminated necrosis of neurons. No lymphocyte infiltration, abnormal cells or signs of meningitis were detected. The girl regained consciousness one week later after cessation of deep sedation with propofol, thiopental and fentanyl. The muscular hypotony of the left side, however, persisted. No long term anticonvulsive therapy was administered. A comprehensive diagnostic workup was performed in search of the underlying dis▶ Table 1 includes the considered diagnoses and the reease. ● sults of the tests performed. A definitive diagnosis was not established. A consecutive treatment in a neuropediatric rehabilitation center resulted in a good recovery of neurologic functions except for residues of left sided hemiparesis. At that time a cranial MRI detected diminution of gray and white matter of the right hemis▶ Fig. 1C). An MRI angiography revealed a rarefication of phere (● the peripheral right anterior, media and posterior vessels. Two days after her discharge from the rehabilitation center the girl felt sick and refused to eat. The laboratory tests revealed thrombocytopenia (72 × 109/L) and a prominent elevation of LDH (1 693 U/L). Leukopenia had returned (2 × 109/L) and liver enzymes were increased to 362 U/L (ASAT) and 195 U/L (ALAT). Other parameters tested such as coagulation values, CRP, lactate, creatinine or urea were repeatedly found to be normal. Concomitantly, the child developed arterial hypertension with proteinuria after which bilateral nephromegaly was diagnosed by ultrasound. The child was re-admitted to the children’s hospital with suspected autoimmune disease based on a positive Coombs test. Within four days the child’s health deteriorated again and she became stuporous. A CCT scan showed a reduced volume of the right hemisphere and an enlargement of the posterior part of ▶ Fig. 1D). Hypodense areas were detected the right ventricle (● in the pons and in the basal ganglia. The symptoms were interpreted as repeated ischemic attacks on the basis of a generalized systemic vasculitis comparable to systemic lupus erythemato- Ege MJ et al. Coincidence of Recurrent Hemiparesis and Detection of ALL … Klin Padiatr 2009; 221: 386–389 Downloaded by: Collections and Technical Services Department. Copyrighted material. Case Report 387 388 Case Report Differential diagnosis Ruled out by – intracerebral bleeding (caused by a tumor, arteriovenous malformations, or other anomalies of the blood vessels) – hemoconcentration – secondary vasculitis e. g. postvaricella angiopathy – secondary vasculitis of other infectious origin – no signs of hemorrhage visible in all CT and MRI scans – predisposing heart disease – hemophilia – hypercoagulation – hemoglobinopathies – idiopathic thrombocytopenic purpura – thrombocytopenic thrombotic purpura – hemolytic uremic syndrome – antileukemic treatment especially with asparaginase – metabolic disorders – brain tumor – normal to low hematocrit/hemoglobin – no varicella-specific IgM/IgG detectable – no IgM/IgG detectable for Herpes simplex, Cytomegaly, Epstein-Barr, Parvo B19, Human Immunodeficiency, Hepatitis A, B, C viruses, Toxoplasma gondii, Candida – normal ECG and echocardiography – no bleeding, no alterations in global coagulation tests – no alterations in global and specific coagulation tests – no signs of sickle cell anemia in blood smears, no hemolysis – no petechiae – no petechiae – no petechiae, no signs of renal failure, no red blood cell fragments in blood smears – symptoms prior to antileukemic treatment – normal serum-pH, normal base excesses – no solid tumor in MRI scans, no malignant cells in brain biopsy sus. Therefore, treatment with steroids was initiated as an emergency treatment. One day later a lumbar puncture revealed a massive increase of the CSF protein, again without pathological increase of the cell numbers. After additional 10 days of ineffective therapy the diagnosis of vasculitis was abandoned, and a bone marrow puncture was performed for suspected ALL. The bone marrow aspirate showed a partial infiltration with acute lymphoblastic leukemia cells (about 60 % of white blood cells in bone marrow smears) displaying the immunophenotype of common ALL (positive for CD 19 (59 %), CD19/CD10 (53 %), CD34/CD19 (28 %), CD22 (59 %), CD24 (79 %), TdT (35 %), negative for Myeloperoxidase, CD14, cytoplasmic IgM). PCR analysis for BCR/ABL fusion gene was negative. An antileukemic chemotherapy was administered according to the ALL-BFM-95 protocol consisting of vincristine, daunorubicin, asparaginase and intrathecal methotrexate treatment. Intensified CNS treatment was not performed because of anticipated toxicity to the previously severely damaged brain tissue. After 7 days of antileukemic therapy the bone marrow response examination revealed less than 5 % blasts, indicating good response to steroids and the chemotherapy regimen. After 12 days of antileukemic therapy proteinuria had decreased and endogenous creatinine clearance recovered (data not shown). Two years after the definite diagnosis and one year of treatment according to BFM protocol, the leukemia was in continuous remission which has now been maintained for almost 10 years. As ▶ Fig. 1E, F), a consequence of the extensive loss of brain tissue (● severe neurological symptoms e. g. inability to walk and speech impairment remain. Discussion & The differential diagnosis of hemiparesis or hemiplegia in childhood includes arteriovenous malformations or other anomalies of the blood vessels e. g. aneurysms, secondary vasculitis like postvaricella angiopathy [1], predisposing heart diseases, hemophilia, hemoglobinopathies, idiopathic thrombocytopenic purpura or thrombocytopenic thrombotic purpura. Metabolic disorders such as homocystinuria and mitochondrial disorders are minor causes. In acute leukemia stroke or stroke like symptoms have been observed in the context of infections or due to anti- leukemic treatment with asparaginase. This induces coagulation disorders [11] with a hypercoagulable state leading to thrombosis mostly of the sinus venosus. Furthermore, elevated leukocyte counts have been described as a cause of leukemia-related neurologic events including CNS hemorrhage and seizures [9]. In patients with cerebral leukemia, i.e. a massive lymphoma like infiltration of the grey and/or white matter, stroke like symptoms have been described as disease-related or therapy-induced complications. Sinus thrombosis, transient gray or white matter ischemia, disseminated microinfarctions and cerebral hemorrhages have been reported [13]. However, it is often impossible to distinguish whether infarctions or hemorrhages are due to the leukemia itself or are a consequence of the chemotherapeutic treatment. Among the 2 169 children enrolled in the ALL-BFM 95 study two deaths from cerebral bleeding have been reported as related to the leukemia itself and not to the treatment [10]. In the presented case the diversity of symptoms and clinical findings prevented or confused a rapid diagnosis. The initial transient leukopenia and anemia were compatible with an infectious episode. The transient hemiparesis and the pes equinus may have mimicked a transient synovitis of the hip as sequelae of the previous infection. However, the first neurologic symptoms can be interpreted as a transitory ischemic attack. Symptoms rapidly resolved without further treatment. At second admission all the above mentioned disease entities were ▶ Table 1). Although the ruled out or were not applicable (see ● clinical features such as anemia, low white cell count, or multifocal clinical symptoms are not typical for stroke an event of primary vascular stroke was considered. As an exclusion diagnosis a transient vasculitis of unknown origin was assumed. However, the brain biopsy did not detect perivascular infiltrates although the rarefication of the peripheral parts of the anterior, medial, and posterior cerebral arteries could be indicative of cerebral vasculitis. Arterial hypertension, proteinuria and bilateral nephromegaly are also compatible with inflammatory disease such as vasculitis. Yet the temporal relationship of onset and resolution of these symptoms with the treatment of leukemia suggests kidney alterations due to the leukemia such as infiltration by leukemic cells. However, on ultrasound imaging, no localized infiltrates could be detected and the presence of proteinuria suggested an inflammatory process as the most likely explanation. Ege MJ et al. Coincidence of Recurrent Hemiparesis and Detection of ALL … Klin Padiatr 2009; 221: 386–389 Downloaded by: Collections and Technical Services Department. Copyrighted material. Table 1 Disease entities ruled out at the patient’s second admission to the hospital. The most frequent manifestation of CNS leukemia is meningeal infiltration. The diagnosis of leukemic meningitis is substantiated by the detection of blast cells in the CSF and by the enhancement of the meninges in the Gadolinium-MRI. In our patient neither cell counts > 10/μl nor blasts were detected at any time point, even before the administration of steroids. Additionally, none of the MRI performed showed a pathologic enrichment of Gadolinium in the meninges. Thus, leukemic meningeosis could be ruled out with high probability. Another manifestation of CNS leukemia is cerebral chloroma (granulocytic sarcoma), which can manifest with stroke symptoms [14]. Chloromas can be seen in MRI as demarcated tumors and are often associated with eosinophilia [7]. These signs were not detected in our patient. With few exceptions chloroma is generally caused by myeloid leukemia. In our patient, however, myeloid origin of the leukemia was later ruled out by immunophenotyping. Primary cerebral lymphomas in childhood are very rare. They have only been described in the context of an acquired or a connatal immunodeficiency [11] or as a complication after transplantations. A parenchymal infiltration of the leukemia is difficult to diagnose, since alterations may not be visible in MRI. Brain biopsies are required to confirm this diagnosis. In our patient a brain biopsy was performed 48 h after emergency craniotomy. As steroids were administered for treatment of the cerebral edema, the presence of leukemia cells in the CNS could have been masked. In patients who underwent stereotactic biopsy for cerebral lymphoma after the onset of the treatment with steroids, lymphoblastoid infiltrations were not found in their histopathological examinations [5]. However, the failure to detect leukemic cells after 48 h of steroid treatment suggests a hypothetic preexisting leukemic CNS infiltration at a very low insignificant level. Increased intracranial pressure and brain edema rapidly developed a few hours after lumbar puncture though the preceding CT scan was inconspicuous. So far there have been no reports of CNS leukemia manifestations such as meningeosis or brain tissue infiltration by blasts leading to increased intracranial pressure. This discrepancy may indicate a major role for an inflammatory response of the brain tissue in our patient. Release of vasoactive or inflammatory cytokines triggered by leukemia cells may have caused these symptoms. Yet this explanation remains speculative, since cytokines were not determined in the acute phase of the disease. Elevated CSF protein may suggest an inflammatory response of the meninges but may also result from ischemia induced brain damage. Since no bacterial or viral infection was present direct induction of this inflammatory response by malignant cells is a possible mechanism for leukemia induced cerebral edema. This case describes a temporal correlation between hemiparesis and the manifestation of lymphoblastic leukemia or cerebral lymphoma. Whether this correlation was causal or not could not be demonstrated. However, it is possible that the leukemia reduced the perfusion in the brain leading to ischemia or damaged brain tissue directly possibly by inflammatory cytokines. Fur- ther characterization of leukemia cells on a molecular level, e. g., by comparative genetic profiling may help to understand this unusual presentation [3]. In this context, gene expression analysis of IL-15 might be relevant, since elevated expression of this gene has been found to be a marker of childhood ALL with CNS affinity [2, 12]. Also in other malignant diseases, such as Ewing sarcoma, genetic profiling is used to detect organ-specific metastasis patterns [8]. Furthermore epigenetic profiling might shed some light onto the (hypothesized) atypical behavior of the leukemia cells [4, 6]. Most of these analyses are provided within the GPOH network. However, in our case a more detailed molecular analysis is hampered by the lack of a sufficient number of stored cells. In conclusion this unusual case suggests that ALL may present with confusing neurological symptoms mimicking ischemia induced stroke in the absence of detectable overt meningeosis and CNS infiltration. Thus, transient focal neurological symptoms may be part of the initial presentation of leukemia in childhood. During the diagnostic workup of such patients an unusual presentation of leukemia should be ruled out by early bone marrow analysis. Conflict of interest: The authors have no conflict of interest to disclose. References 1 Askalan R et al. Chickenpox and stroke in childhood: A study of frequency and causation. Stroke 2001; 32: 1257–1262 2 Cario G et al. High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS. J Clin Oncol 2007; 25: 4813–4820 3 Faber J et al. Defining leukemia stem cells in MLL-translocated leukemias: implications for novel therapeutic strategies. Klin Padiatr 2007; 219: 306–311 4 Fruhwald MC et al. The epigenetics of cancer in children. Klin Padiatr 2008; 220: 333–341 5 Geppert M et al. Glucocorticoid therapy obscures the diagnosis of cerebral lymphoma. Acta Neuropathol 1990; 80: 629–634 6 Gruner I et al. Epigenetic profiling of pediatric cancers. Klin Padiatr 2007; 219: 185 7 Henson JW et al. CNS chloromas in patients presenting with eosinophilia. Neurology 1989; 39: 1386–1388 8 Knizia H et al. Identifying cellular mechanisms of organ-specific metastasis of Ewing sarcoma. Klin Padiatr 2008; 220: 203 9 Moricke A et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111: 4477–4489 10 Packer RJ et al. Cerebrovascular accidents in children with cancer. Pediatrics 1985; 76: 194–201 11 Rodriguez MM et al. Epstein-Barr virus-associated primary central nervous system lymphoma in a child with the acquired immunodeficiency syndrome. A case report and review of the literature. Arch Pathol Lab Med 1997; 121: 1287–1291 12 Stanulla M et al. High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the central nervous system. Klin Padiatr 2007; 219: 193 13 Walker RW. Neurologic complications of leukemia. Neurol Clin 1991; 9: 989–999 14 Zentner J et al. Intracerebral chloroma complicating acute monocytic leukemia. Neurochirurgia (Stuttg) 1992; 35: 60–62 Ege MJ et al. Coincidence of Recurrent Hemiparesis and Detection of ALL … Klin Padiatr 2009; 221: 386–389 Downloaded by: Collections and Technical Services Department. Copyrighted material. Case Report 389